Project Summary This BRG R01 (PAR-16-242) application aims to greatly improved spatial and temporal resolution: Penetrating electrical stimulation arrays are a crucial component of basic neuroscience research and human neuroprosthetics. A challenge with this technology is achieving a highly localized stimulated area of the same neurons over weeks and months. However, implantation of cortical microelectrodes causes a reactive tissue response, which results in a degradation of the preferred functional performance over time, thus limiting the device capabilities. Current electrical stimulation implants are tethered to the skull, which chronically increases the impact of mechanical mismatch, causes neural degeneration around the implant, increases the chance of infection, increases the chance of mechanical trauma induced failure as well as shifting of the electrode position, and increases in electrical impedances from glial scarring. In turn, the electrical stimulation loses its effectiveness to excite neural tissue, making longevity a challenge. Simply increasing the electrical current to compensate can lead to permenant damage to the tissue and/or the electrode. This proposal proves an innovative strategy that uses leading-edge biocompatible materials to develop innovative ?Wireless Axon? electrodes that are ultra-small and untethered, with bioactive surfaces and nanostructured materials for enhanced signal transduction to electrically excitable tissue. The project aims to decouple the mechanical requirements necessary in traditional microstimulation technology and improve spatial selectivity of activated neurons for stable long-term electrical stimulation. The guiding hypothesis is that decoupling the mechanical tether will improve tissue integration, while immobilized biomolecules will effectively intervene with the reactive tissue response as well as improve electrode-neuron signal-coupling and selectivity. This project is likely to make significant contributions through developing advanced neural probes for long- term (permanent), high quality, and selective neural stimulation. These could potentially lead to paradigm shifts in both neuroscience research and clinical neuroprosthetics and neurostimulation through creating the capability of activating specific neurons for long periods of time with great precision. Our guiding hypothesis is that the product of the combined benefit is synergistic and greater than the sum of its parts. The outcomes of this project are also likely to establish new biologically inspired paradigms for creating long-lasting, high-fidelity neural interfaces with biomimetic materials as well as new paradigms for longitudinally probing neural circuits, particularly for the study of learning and plasticity. Several variations of the technology developed in this project is expected to be compatible with optogenetics. This project would impact both the neuroscience research community, and clinical scientists (neurosurgeons, neurologists, and patients) that use and benefit from neuroprosthetic- and neurostimulation-based treatments interventions.